NM_004722.4:c.45C>G

Variant names:

• chr7-100101759-C-G
• rs370677112
• NM_004722.4:c.45C>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Moderate BP6_Moderate BP7

The NM_004722.4(AP4M1):​c.45C>G​(p.Leu15Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000098 in 1,530,300 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. L15L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000082 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: AP4M1 NM_004722.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.97
• Publications: 0 publications found

Genes affected

AP4M1 (HGNC:574): (adaptor related protein complex 4 subunit mu 1) This gene encodes a subunit of the heterotetrameric AP-4 complex. The encoded protein belongs to the adaptor complexes medium subunits family. This AP-4 complex is involved in the recognition and sorting of cargo proteins with tyrosine-based motifs from the trans-golgi network to the endosomal-lysosomal system. [provided by RefSeq, Jul 2008]

MCM7 (HGNC:6950): (minichromosome maintenance complex component 7) The protein encoded by this gene is one of the highly conserved mini-chromosome maintenance proteins (MCM) that are essential for the initiation of eukaryotic genome replication. The hexameric protein complex formed by the MCM proteins is a key component of the pre-replication complex (pre_RC) and may be involved in the formation of replication forks and in the recruitment of other DNA replication related proteins. The MCM complex consisting of this protein and MCM2, 4 and 6 proteins possesses DNA helicase activity, and may act as a DNA unwinding enzyme. Cyclin D1-dependent kinase, CDK4, is found to associate with this protein, and may regulate the binding of this protein with the tumorsuppressor protein RB1/RB. Alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 7-100101759-C-G is Benign according to our data. Variant chr7-100101759-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2742210.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=2.97 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004722.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP4M1	NM_004722.4	MANE Select	c.45C>G	p.Leu15Leu	synonymous	Exon 1 of 15	NP_004713.2
	AP4M1	NM_001438831.1		c.-488C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 16	NP_001425760.1
	AP4M1	NM_001438832.1		c.-415C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 16	NP_001425761.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP4M1	ENST00000359593.9	TSL:1 MANE Select	c.45C>G	p.Leu15Leu	synonymous	Exon 1 of 15	ENSP00000352603.4	O00189
	AP4M1	ENST00000421755.5	TSL:1	c.45C>G	p.Leu15Leu	synonymous	Exon 1 of 16	ENSP00000412185.1	O00189
	MCM7	ENST00000343023.10	TSL:1	c.-465G>C		5_prime_UTR	Exon 1 of 9	ENSP00000344006.6	P33993-2

Frequencies

GnomAD3 genomes AF: 0.0000822 AC: 12 AN: 146070 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000299

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000160 AC: 4 AN: 250602 AF XY: 0.00

Gnomad AFR exome AF: 0.000247

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000217 AC: 3 AN: 1384230 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 687790

African (AFR) AF: 0.0000994 AC: 3 AN: 30168

American (AMR) AF: 0.00 AC: 0 AN: 42800

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23570

East Asian (EAS) AF: 0.00 AC: 0 AN: 35870

South Asian (SAS) AF: 0.00 AC: 0 AN: 85454

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47478

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5378

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1058312

Other (OTH) AF: 0.00 AC: 0 AN: 55200

GnomAD4 genome AF: 0.0000822 AC: 12 AN: 146070 Hom.: 0 Cov.: 33 AF XY: 0.0000563 AC XY: 4 AN XY: 71088

African (AFR) AF: 0.000299 AC: 12 AN: 40134

American (AMR) AF: 0.00 AC: 0 AN: 14842

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3392

East Asian (EAS) AF: 0.00 AC: 0 AN: 4678

South Asian (SAS) AF: 0.00 AC: 0 AN: 4258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9552

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65972

Other (OTH) AF: 0.00 AC: 0 AN: 2046

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000831

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary spastic paraplegia 50 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	11
DANN	Benign	0.92
PhyloP100		3.0
PromoterAI		0.035	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs370677112; hg19: chr7-99699382;